A new study by researchers at UC San Francisco and UC Davis has uncovered why women’s bones remain relatively robust during breastfeeding, even though calcium is removed from the bones for milk production. The researchers showed in mice that a hormone they called Maternal Brain Hormone (CCN3) increases bone density and strength and could contribute to the treatment of osteoporosis and bone fractures in the general population.
More than 200 million people worldwide suffer from osteoporosis, a serious weakening of the bones that can lead to frequent fractures. Women are particularly at risk of developing the condition after menopause because of declining levels of estrogen, a sex hormone that normally promotes bone formation. Estrogen levels are also low during breastfeeding, but osteoporosis and bone fractures are much rarer during this time, suggesting that something other than estrogen is promoting bone growth.
“One of the most remarkable aspects of these findings is that if we had not studied female mice, which is unfortunately the norm in biomedical research, we might have missed this discovery,” said Holly Ingraham, senior author of the new study and professor of molecular and cellular pharmacology at UCSF. “This underscores the importance of studying both male and female animals throughout their lifespan to gain a complete understanding of biology.” The results were published in Nature.
The hormone that strengthens bones is only produced during breastfeeding
Ingraham’s lab previously found that in female mice, but not males, blocking a particular estrogen receptor on certain neurons in a small area of the brain led to large increases in bone mass. They suspected a hormone in the blood was responsible for strengthening bones, but they couldn’t find it at the time, and the search continued during the COVID-19 pandemic.
In the new study, Ingraham and his collaborators conducted an exhaustive search for this bone-building hormone and ultimately identified CCN3 as the responsible factor in mutant females. The team was initially surprised by this result, as CCN3 did not fit the typical profile of a hormone secreted by neurons.
A hydrogel patch applied to the site of a bone fracture to slowly release the hormone CCN3 stimulated the formation of new bone tissue, promoting its healing.
Their doubts disappeared when they found CCN3 in the same brain region in lactating female mice. Without CCN3 production in these select neurons, lactating females rapidly lost bone and their offspring began to lose weight, confirming the hormone’s importance in maintaining bone health during lactation. Based on this discovery, they now refer to CCN3 as Maternal Brain Hormone (MBH).
Generate new bone cells and heal fractures
When strategies to increase circulating CCN3 were implemented in young adult and aged mice, both female and male, their bone mass and strength increased significantly over the course of weeks. In some females that were deprived of estrogen or were very old, CCN3 was able to more than double bone mass.
When Ingraham’s scientific collaborator, Thomas Ambrosi, an assistant professor of orthopedic surgery at UC Davis, tested these bones, he was surprised by their strength. “In some situations, highly mineralized bones are not better — they can be weaker and break more easily,” he explained. “But when we tested these bones, they turned out to be much stronger than usual.” Ambrosi closely examined the stem cells within the bones responsible for generating new bone tissue and found that when these cells were exposed to CCN3, they were much more likely to generate new bone cells.
To test the hormone’s ability to aid in bone healing, the researchers created a hydrogel patch that could be applied directly to the site of a bone fracture, where it would slowly release CCN3 over two weeks. In older mice, bone fractures typically do not heal well. However, the CCN3 patch stimulated the formation of new bone tissue at the fracture site, contributing to youthful fracture healing.
“We’ve never been able to achieve this type of mineralization and healing outcome with any other strategy,” Ambrosi said. “We’re really excited to move forward and potentially apply CCN3 in the context of other problems, such as cartilage regeneration.” The researchers plan to conduct future studies on the molecular mechanisms of CCN3, its levels in lactating women, as well as the hormone’s potential to treat a variety of bone conditions.
“Bone loss occurs not only in postmenopausal women, but also in breast cancer survivors taking certain hormone blockers; in highly trained young elite athletes; and in older men whose relative survival rate is worse than that of women after a hip fracture,” Ingraham said. “It would be incredibly exciting if CCN3 could increase bone mass in all of these scenarios.”
